tbuckley/cabot-search huggingface dataset:
Genomic profile by liquid biopsy of Peruvian patients with lung cancer.
Authors: Marco Galvez-Nino, Katia Roque Perez, Melanie Wendy Castro, Rossana Ruiz, Natalia Valdivieso, Ofelia Coanqui, Mivael Olivera Hurtado de Mendoza, Edgar Amorin, Luis Mas
Journal: Journal of Clinical Oncology (2022)

e15027 Background: The optimal treatment of advanced NSCLC patients is currently led by genomic profiling with the goal of detecting actionable mutations with an approved targeted therapy. However, tissue DNA samples are not always available to perform this assays. In this context, liquid biopsy has emerged as a valuable tool for providing the best treatment option. Methods: Retrospective study held at Instituto Nacional de Enfermedades Neoplasicas (INEN), Lima - Peru, between January 2019 and September 2021 to assess the genomic profile of 190 newly diagnosed advanced NSCLC patients through liquid biopsy. Blood samples were profiled with the FoundationOne Liquid Biopsy assay. We describe frequency of pathogenic and targetable genetic alterations, as well as the survival outcomes. Genomic and clinical data were recorded from clinical files. Results: The median age was 63 years (26-90), 66.3% were women, 15.3% smokers, 26.3% had exposure to biomass, 22.6% had a first-degree family history of cancer. The most frequent histological type was adenocarcinoma (86.8%). Regarding genomic profile, 183 patients (96.3%) had at least one pathogenic genetic alteration, the most frequent altered genes were TP53 (54.7%), EGFR (50.5%), DNMT3A (17.9%), KRAS (9.5%) and NF1 (6.8%). 116 patients (61%) had a targetable mutation: EGFR Ex19del/ins (27.4%), EGFR L858R/L861Q (17.9%), ALK rearrangements (5.8%), BRAF V600E (3.2%), RET fusions (1.6%), METex14 skipping (1.6%), KRAS G12C (1.6%), ROS 1 (1.1%), and NTRK (0.5%). Of these, 71 patients (65.5%) were able to access target therapy. For the latter, estimated median PFS and OS were 14.0 months (9.3 – 18.6) and 17.8 months (8.2 – 27.4), respectively. Conclusions: Peruvian NSCLC patients represent a population with a high frequency of pathogenic and targetable mutations, being EGFR mutations and ALK rearrangements the most prevalent ones. Despite limited access, a great proportion of patients received target therapy, achieving remarkable survival.
A biological network approach for mining target genes in EBV-positive gastric cancer.
Authors: Williams Fernandes Barra, Ronald Matheus da Silva Mourao, Jessica Costa Silva, Ana Karyssa Anaissi, Samia Demachki, Geraldo Ishak, Danielle Queiroz Calcagno, Fabiano Cordeiro Moreira, Paulo Pimentel Assumpção
Journal: Journal of Clinical Oncology (2022)

4056 Background: Epstein–Barr virus (EBV) discriminates a molecular group of gastric cancer (GC) that seems to have peculiar treatment responses and prognosis. Nevertheless, the gene expression pattern of such tumors needs additional investigations due to the heterogeneity of the tumor microbiome and the small number of studied samples. Biological networks analysis of gene expression patterns, in this complex scenario, might lead to the discovery of putative "hubs" genes, supposed to have important roles in cancer occurrence and consequences. This study aimed to explore the biological value of hub genes in EBV-positive gastric cancer patients. Methods: Fresh tumor samples collected during gastrectomies from individuals with gastric adenocarcinoma (n = 41, 59.0±11.0 years) were included. Gene expression of tumor samples was evaluated in the Illumina sequencing platform. A weighted correlation network analysis (WGCNA) was used to find highly correlated gene patterns. The gene's correlation to EBV status was also explored, including eight EBV positive and 33 EBV negative cases. Gene Ontology (GO) term enrichment was performed to predict the involved biological functions. The expression level of the hubs gene was measured by differential expression analysis. Results: A gene cluster including 636 genes able to discriminate EBV status (ρ = 0.65, p-value = 6e-05) was identified. GO analysis (padj &lt;0.05) showed that this cluster of genes is related to T cell activation, regulation of immune effector process, and response to the biotic stimulus. In this cluster, 54 genes were differentially expressed (log2FoldChange (FC) &gt;1 and padj&lt; 0.05). The top hub genes were LAPTM5, PTPN22, C1QA, CD84, CD53, ADAMDEC1, DPYD, TYROBP, RARRES3, IFI16, CYBB, CMKLR1, PHF21A, GPNMB, and C1QC, according to cluster significance and gene expression level. In positive EBV-GC, all hub genes were overexpressed (FC 1.24 - 2.49) (Table). The average area under the ROC curve (AUC) for hub genes was 0.9 (0.84-0.99). Overexpression of LAPTM5 (p-value = 0.013) and DPYD (p-value =0.0065) and low expression of ADAMDEC1 (p-value = 0.05) were strongly related to poor survival outcome. Conclusions: EBV-positive status was correlated with overexpression of hub genes. Genes found in this investigation have high sensitivity and specificity to discriminate EBV status in GC. Some of them seem to be related to patients' survival, opening an avenue for future scientific explorations in this field. The biological network's approach may be a promising tool for mining target genes for potential clinical applications. [Table: see text]
The efficacy and safety of sintilimab plus regorafenib in refractory metastatic colorectal cancer.
Authors: Rongrong Li, Zhenyang Liu, Xianli Yin, Deyu Zeng, Shaofeng Jiang, Wu Liu
Journal: Journal of Clinical Oncology (2022)

e15546 Background: To explore the efficacy and safety of sintilimab plus regorafenib in refractory metastatic colorectal cancer (mCRC). Methods: We retrospectively evaluated the outcomes of the patients with mCRC who received at least one cycle of sintilimab plus regorafenib in the Hunan Cancer Hospital between July 2019 and June 2021. These patients had previously received at least two lines of standard chemotherapy including fluorouracil, oxaliplatin, and irinotecan with or without targeted drugs such as bevacizumab and cetuximab.The primary end point was overall survival (OS). Results: With a median follow-up of 6.00 months (range 0.70-22.47), the median overall survival (mOS) and progression-free survival (mPFS) were 9.00 months (95%CI: 5.00-NA) and 3.30 months (95%CI: 2.50-4.70).There was no significant difference in OS and PFS between patients with and without liver metastases,the mOS was 9.00 months 95%CI:[8.00-NA] vs 8.00months 95%CI:[5.00-NA]; P= 0.38, the mPFS was 3.87 months 95%CI:[3.10-13.70] vs 2.79 months 95%CI:[2.37-5.03]; P= 0.12.Cox multivariate regression analysis demonstrated that cycles of regorafenib plus PD-1 was a significant independent risk factor for the OS ( P0.001),and it was a positive factor that there was just one metastatic site ( P= 0.0038).Patients who had previously undergone surgery were better than those who had not ( P= 0.0470).Seven patients got partial response and another 9 patients got stable disease in the 35 patients who were evaluated, but no complete response. Thus the objective response rate(ORR) was 20.0% and the disease control rate(DCR) was 45.7%.The incidence of grade 3/4 adverse evevts was 10.6%. Conclusions: The combination of sintilimab plus regorafenib had a manageable safety profile and promising efficacy in refractory mCRC patients. This combined therapy needs further prospective studies to verify the outcomes.[Table: see text]
Natural distribution of genomic alterations correlated with the resistance to KRAS<sup>G12C</sup> inhibitor in Chinese colorectal cancer.
Authors: Ke He, Yuerong Chen, Fei Liu, Liheng Li, Chaosheng Wu, Xiu Lv, Xinyi Liu
Journal: Journal of Clinical Oncology (2022)

e15550 Background: KRAS inhibitors exhibited promising efficacy as systemic therapy in KRAS G12C-mutant colorectal cancers (CRC) lately. Recent studies have revealed a number of genomic alterations related to acquired resistance to this type of drugs. The discovered resistant gene mutations include: 1. Novel acquired secondary KRAS mutations within the adagrasib-binding pocket such as Y96C, H95D/Q/R, R68S, 2. Activating mutations in genes ( KRAS, BRAF, MAP2K1) MAPK signaling pathway, 3. Oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3, 4. Gene amplifications in KRAS, MET, MYC. Although found as acquired resistance mechanism to KRAS inhibitors, these genomic alterations might be primary or secondary in the setting of other type of therapies. Characterizing the natural distribution of these genomic alterations in cancer patients would contribute to clarifying the application potential of KRAS inhibitors. We herein performed a large-sample size analysis in Chinese colorectal cancer. Methods: A total of 9385 early-stage, late-stage, treated or treatment-naive CRC were included in this analysis. Calling of single nucleotide variants (SNV), copy number variants (CNV), insertion/deletions (indels), fusions and evaluation of tumor mutational burden (TMB) were performed using a wide panel next-generation sequencing (NGS) testing. Results: 43.4% (4069/9385) cases were KRAS-mutant in this cohort. KRAS G12C account for 5.8% (236/4069) in all KRAS-mutant CRC, and 15.7% (37/236) were harbored the above resistance genomic alterations. Fifteen KRAS G12C-mutant CRC were detected to have activating MAPK mutations, including G12D/V (n = 6), G13D (n = 3), Q61H (n = 6), NRAS Q61K (n = 3), MAP2K1 K57T (n = 3), and BRAF V600E (n = 4). Ten KRAS G12C-mutant CRC were detected to have oncogenic fusions, including TGFBR2- CACNA1D (n = 3), TPM4- ALK (n = 1), FGFR3- TACC3 (n = 1), ETV6- SNRPC (n = 1), KAZN- PAX7 (n = 1), NRG1- TTC12 (n = 1), TCF7L2- EWSR1 (n = 1) and ERBB2 arrangement (n = 2). It is noteworthy that a single case was with 5 gene arrangement events in 17q ( ERBB2- ZPBP2, IKZF3- ERBB2, PGAP3- ERBB2, RARA- ERBB2, RARA- GRB7). Thirteen KRAS G12C-mutant CRC were detected to have amplifications in KRAS (n = 5), MYC (n = 5) and MET (n = 4) genes. TP53 (81%), APC (65%) and PIK3CA (32%) were the utmost frequent somatic mutational genes in this subgroup of CRC. In addition, all cases were microsatellite stable (MSS). Tumors harboring fusion variants showed relatively high TMB level in this cohort. Conclusions: Our analysis results indicate about 15% KRAS G12C-mutant Chinese CRC were probable resistant to KRAS G12C inhibitor. One-third of these patients had co-existed oncogenic fusions and higher TMB levels, suggesting possibilities for other therapeutic choices.
Characteristics and outcomes of COVID-19 in adult cancer patients: Tertiary cancer center experience.
Authors: Hazim Ababneh, Fadwa Alqadi, Mohammad Ma'koseh, Khalid Halahleh, Layan Abo abed, Mohammad Akkawi, Kamal Al-Rabi, Hikmat Abdel-Razeq
Journal: Journal of Clinical Oncology (2022)

e13601 Background: The COVID-19 pandemic has led to deteriorated outcomes among immunocompromised patients, significantly impacting cancer patients. However, little is known about the impact of the COVID-19 pandemic on cancer patients in low and middle-income countries. Therefore, we sought to investigate the characteristics and clinical outcomes of cancer patients with COVID-19 treated at a single institution. Methods: A retrospective chart review was performed for cancer patients treated at King Hussein Cancer Center. Patients who were diagnosed with laboratory-confirmed SARS-CoV-2 infection by Real-time Polymerase chain reaction test between April 2020 and October 2020 were identified. Results: Overall, 327 COVID-19-infected cancer patients were included. At the time of COVID-19 diagnosis, the median age was 55 years (range, 18-87 years), 146 patients (45%) were males. The most common neoplasms were breast cancer (n = 90, 27.5%), gastrointestinal cancers (n = 60, 18.3%), and lymphoma (n = 36, 11%). The majority of patients had comorbidities (n = 200, 61%), of which hypertension and diabetes mellitus were the most common. Testing reason was presence of symptoms in 183 (56%) patients, previous exposure in 10 (3.1%), and before elective procedure in 142 (43.4%). 118 patients (56.5%) were hospitalized and 18 patients (5.5%) required admission to the intensive care unit (ICU). At the time of the last follow-up, 76% (n = 249) remained alive, and 24% (n = 78) died, among which death was considered to be COVID related in 41 (52.5% of deaths). Mortality was significantly increased in patients with comorbidities (29%, vs 15.7 %; p = 0.008), the use of cardiac medications (34.3% vs. 18.1%; p = 0.001), active cancer status vs. remission (28.2% vs 11.6% p = 0.002), receiving chemotherapy in the last four weeks (27.6% vs 16.4%, p = 0.028), and when testing reason was the presence of symptoms vs exposure and elective (37.7% vs. 10% and 7.7% p = &lt; 0.001) respectively. Chemotherapy was delayed in 109 (33.4%) patients and permanently discontinued in 57 (17.5%) patients. Among patients required hospitalization and needed ICU admission, mortality rates were 55.1% and 88.9% respectively. Conclusions: COVID-19 infection is associated with significant mortality and negatively affects treatment plans in cancer patients. A follow-up study will be needed to evaluate the effect of vaccination on the outcomes.
Multicenter retrospective study of clinical genetic testing in patients with sarcoma.
Authors: Helen Catherine Wilbur, Erin Frances Cobain, Georgia L. Wiesner, Elizabeth J. Davis, Rashmi Chugh
Journal: Journal of Clinical Oncology (2022)

10511 Background: Sarcomas are rare and diverse malignancies with a subset developing in the context of heritable cancer predisposition syndromes. Data surrounding the frequency of inheritance and patient/genomic findings are limited. We aimed to describe the characteristics of patients with sarcoma referred for clinical genetic testing and to determine the prevalence of pathogenic/likely pathogenic germline variants (PGV/LPGV). Methods: We performed retrospective chart reviews of patients with sarcoma referred to Michigan Medicine Cancer Genetics Clinic between 12/2006 and 1/2020 and Vanderbilt Hereditary Cancer Clinic between 1/2005 and 1/2019. Reviewers obtained medical/family history, cancer phenotype, and results of germline genetic testing. Descriptive analyses were performed to assess the prevalence of germline variants classified as pathogenic/likely pathogenic according to American College of Medical Genetics criteria. Associations with clinical factors were tested for using Fisher’s exact test or Wilcoxon rank-sum test. Results: One-hundred sixteen patients with sarcoma underwent genetic evaluation during a 15-year period. Mean age at time of visit was 46 years (SD, 17.6 years; range, 1-80 years). Sixty-nine patients (59%) were female. The most common reasons for referral were personal history of multiple malignancies (n = 69, 59.4%), first degree relative (FDR) with malignancy (n = 67, 57.7%) and young age at diagnosis (age ≤ 18, n = 18, 15.5%). Forty-eight patients (41.4%) had both a history of multiple malignancies and a FDR with a malignancy. Eight patients had a FDR with sarcoma (6.9%). Of the 110 patients who underwent germline testing, 53 patients (48.2%) had a PGV/LPGV. Identified germline variants and frequencies are listed in the Table. There was no statistical significance between young age at diagnosis, history of personal malignancies, FDR with sarcoma, FDR with one or more malignancies, or multiple FDRs with malignancy and presence of a PGV/LPGV. Conclusions: In this multicenter study, approximately half of patients with sarcoma referred for cancer genetic testing had a PGV/LPGV associated with hereditary predisposition to cancer. There was no identified positive predictive factor for germline variants. Though TP53 was the most common, over 20 genetic variants were identified, supporting the consideration of multigene panel testing. Our study is limited to patients who were both referred to and attended genetic evaluation. Yet, the high frequency of pathogenic germline variants observed highlights the necessity for further investigation of the prevalence of and predictive factors for germline mutations in all sarcoma patients. Identified germline variants. [Table: see text]
Real-world changes in the clinical management of resected stage III melanoma at high risk of local recurrence in the era of modern systemic therapies.
Authors: Seth Kibel, Nathan Kuehne, Mauricio Ribeiro, Thiago Pimentel Muniz, Philip Wong, Anna Spreafico, David Hogg, Sam Saibil, Alexander Sun, David Y. Mak, Diana Gray, Marcus O. Butler
Journal: Journal of Clinical Oncology (2022)

e21575 Background: Adjuvant systemic therapies (ST) for patients with resected stage III melanoma have improved relapse-free survival; however, the role of adjuvant radiotherapy (RT), previously the mainstay adjuvant treatment, is undefined in the modern ST era. Real-world data detailing clinical practice changes and its impact on outcomes are needed to help inform the choice of adjuvant therapy for patients with resected stage III melanoma. Methods: In this single-center retrospective study, patients from Princess Margaret Cancer Centre with resected stage III cutaneous melanoma treated between 2010 and 2019 and fitting the 2016 Cancer Care Ontario guidelines for adjuvant RT were included. Demographic, pathological, and clinical data were abstracted from electronic medical records. PFS was defined as the time from lymph node dissection to local-regional recurrence in the treated nodal basin or distant recurrence. OS was defined as time from lymph node dissection to death by any cause. The Log-rank method was applied to assess survival endpoints. A p-value &lt; 0.05 was considered statistically significant. Results: From 4,959 records reviewed, 109 patients were identified. Median age at time of surgical resection was 59.4 years (23.6-89.8), and 74 (68%) were male. Type of adjuvant therapy and number of local-regional recurrences (LR) are expressed in the table. The median follow-up among those alive at last follow-up was 54.2 months (range 1.9-122). The proportion of patients receiving adjuvant RT was higher between 2010 and 2014 than it was between 2015 and 2019 (59% to 26%), whilst the proportion of those receiving adjuvant ST progressively grew (3% to 50%). LR &gt; 90 days following lymph node dissection as the first site of relapse or synchronously with progression to metastatic disease was rare in patients treated with either adjuvant RT (6.8%) or adjuvant ST (14.3%, chi-square p = 0.33). Median progression free survival was 12.3 months in patients treated with adjuvant RT and 43.8 months in patients treated with adjuvant ST (p = 0.007). Overall survival was not significantly different (p = 0.08). Conclusions: The advent of ST has changed our institution’s clinical practice with ST replacing RT as the primary adjuvant treatment modality. Our data suggests that in the current adjuvant treatment landscape, omission of RT does not seem to increase rates of local-regional recurrences, and patients with resected stage III melanoma can be safely spared from adjuvant RT without detrimental effect on survival.[Table: see text]
Irinotecan combined with Panitumumab or cetuximab as third-line treatment for metastatic colorectal cancer.
Authors: Maria Ignez Braghiroli, Maria Fernanda Batistuzzo Vicentini, Leonardo Gomes da Fonseca, Karla Teixeira Souza, Renata Colombo Bonadio, Oddone Freitas Melro Braghiroli, Maria Cecília Machado Mathias, Aley Talans, Maria Elizabeth Zambrano Mendoza, Juliana Goes Martins, Jorge Sabagga, Camila Venchiarutti Motta Venchiarutti Moniz, Paulo Marcelo Hoff
Journal: Journal of Clinical Oncology (2022)

e15551 Background: Literature suggests that the addition of cetuximab can overcome the resistance to irinotecan treatment for metastatic colorectal cancer (mCRC). It is unknown if the combination of panitumumab with irinotecan could also revert treatment resistance and offer a better response rate after progression on irinotecan monotherapy. In this study, we aim to compare the impact of panitumumab plus irinotecan (P+I) or cetuximab plus irinotecan (C+I) on overall survival as a third line mCRC treatment. Methods: This is a single institution, retrospective cohort analysis, evaluating the overall survival of mCRC patients exposed to an anti-EGFR antibody plus irinotecan, upon progression on irinotecan monotherapy. Overall survival function was estimated using the Kaplan-Meier method and compared using the log-rank test. Results: We identified 460 patients with mCRC that fulfilled inclusion criteria, treated between July 2008 and April 2018. One hundred eighty-three (183) patients received (I+C), and 277 received (I+P). Upon diagnosis, the median age was 55.9 years (range, 19 - 83 years), with a male to female ratio of 1.3:1. All patients received the combination of irinotecan and anti-EGFR targeting antibodies for at least one cycle (D1 and D15). Partial response occurred in 22.6% of patients [23.5% for (I+C) and 22.0% for (I+P)], and 25,2% had stable disease [27.8% for (I+C) and 23.6% for (I+P)]. Interestingly, response rate in patients with right-sided tumors was 3.3% in the (I+C) regimen and 14.3% in the (I+P) regimen. The disease control rate was 50.3% in the (I+C) combination and 45.7% in the (I+P) combination (p = 0.358). The median overall survival (mOS) for all patients was 9.63 months, 8.97 to the group C+I and 10.74 to P+I (p = 0.73). Regarding primary tumor location, the mOS was 6.34 mo for right-sided tumors and 10.74 mo for left-sided tumors (p = 0.022). The 3-year survival rate was 5.6% for the (C+I) treated patients and 3.2% for (P+I). Conclusions: (P+I) and (C+I) combinations showed similar response rate and mOS as a third-line treatment for mCRC, suggesting that both anti-EGFR agents can be used in this setting. A perceived tendency for a superior response with the (I+P) regimen in right-sided tumors might warrant further investigation in prospective studies.
Using tandem repeat genomic features for cancer signal detection across multiple cancer types.
Authors: Victor Solovyev, Sidney Tobias, Edmund Wong, Shun H Yip, Cheuk Ying Tang
Journal: Journal of Clinical Oncology (2022)

e13586 Background: Next generation sequencing methods enable the identification of molecular signatures predictive of cancers. Large-scale cancer genomic projects such as The Cancer Genome Atlas (TCGA) molecularly characterized over 20,000 primary cancer and matched normal samples spanning 33 cancer types. The resulting data provides an opportunity to uncover a list of recurrent genomic aberrations, such as mutations, amplifications, insertions, and deletions, that can be used in machine learning models for multiple cancer type detection. Previous research has demonstrated significant variability in the stability of tandem repeat sequences between different cancer types, with consequences for gene expression, which is consistent with known oncogenic mechanisms. Methods: Our approach identifies a set of tandem repeats from whole-exome sequencing data to analyze, and computes differences relative to the reference genome in the cancer patients’ samples. For each tandem repeat sequence (referred to hereafter as TRS), we count the frequency of occurrence of the TRS in its reference state, as well as its specific variations (deletions/insertions) in each cancer patient exome sequence. These TRS read counts are the features for our cancer type prediction model. Through filtering out features of lower significance, we condense our training and testing datasets down from a half million possible features per sample, to merely thousands of features common across all the samples. From there, we train multi-class one-vs-all logistic regression models rapidly and optimize our feature selection and preprocessing to maximize predictive accuracy. Results: As can be seen in the Table below, our logistic regression model trained on TRS features enables us to predict cancer type with high accuracy in TCGA patient samples (as compared with random prediction accuracy, which would be approximately 10%). Conclusions: This approach lays the groundwork for novel TRS-based genetic tests for early detection and diagnosis of multiple types of cancer. [Table: see text] [Table: see text]